AB1182 SPECIALIZED PRO-RESOLVING MEDIATORS (SPMS) AND INFLAMMATORY NETWORKS IN PATIENTS AFFECTED BY ADULT ONSET STILL’S DISEASE (AOSD) AND COVID-19
Authors: L. Navarini, M. Vomero, O. Berardiucrti, D. Currado, A. Marino, A. Biaggi, S. DI Donato, F. Ursini, P. Ruscitti, R. Meliconi, P. Cipriani, A. Iagnocco, A. Afeltra, R. Giacomelli
Journal: Annals of the Rheumatic Diseases (2022)

Background Uncontrolled systemic inflammation characterizes COVID-19 and autoinflammatory diseases such as adult-onset Still’s disease (AOSD). Biosynthesis of pro-resolving mediators (SPMs), i.e. lipoxins (LX), resolvins (Rv), protectins (PD), and maresins (MaR), ensures inflammation shutdown and tissue repair, limiting neutrophils recruitment and stimulating macrophages to remove apoptotic cells. Among protectins, reduction of PD1 was found in the lungs of mice infected with the H5N1 influenza virus and experimental treatment with PD1 resulted in increased animals’ survival (Morita M et al 2013). Objectives We investigated the effects of SPMs in pathogenesis and clinical evolution of AOSD and compared these data with mild and severe COVID-19. Finally, we analyzed the potential role of PD1 in modulating the inflammatory response of macrophages obtained from AOSD patients, COVID-19 patients and healthy donors (HDs). Methods 21 patients hospitalized for COVID-19 (10 ICU and 11 hospitalized in medical clinical unit) and 13 patients with AOSD were enrolled. Plasma PD1 levels from patients and controls were analyzed by ELISA, and monocytes-derived macrophages were polarized into M1 and M2 phenotype. We analyzed the effect of PD-1 on macrophages differentiation. At 10 days, macrophages were analyzed for surface expression of subtypes markers by flow cytometry. Cytokines production was measured in supernatants by Bio-Plex Assays. Peripheral blood mononuclear cells (PBMCS) from 3 AOSD patients, 2 COVID-19 patients and 3 HDs were obtained. Next-generation deep sequencing was then performed to identify the differences in PBMCs transcripts profiles. Results AOSD patients with systemic scored (SS) ≥1 showed an increase of PD1 levels compared to AOSD patients with lower systemic score (p=0.04) (Figure 1A). Similarly, plasma levels of PD1 were increased in COVID-19 patients independently from their clinical subsets, compared to HDs (p=0.02). I n vitro treatment with PD1 of monocytes-derived macrophages from AOSD and COVID-19 patients induced a significant increase of M2 polarization vs control (p&lt;0.05) (Figure 1B). Furthermore, a significant release of IL-10 and CCL4 from M2 macrophages was observed when compared to control (p&lt;0.05) (Figure 1C). In the transcriptomes from 3 AOSD patients (2 mild and 1 severe), 2 COVID-19 patients (1 mild and 1 ICU) and 2 HDs, we observed that genes involved in inflammation, lipid catabolism and monocytes activation were specifically dysregulated in AOSD and COVID-19 patients when compared to HDs. Among them pla2g15, pla2g12a, pla2g2d, involved in mobilization of SPMs precursors, were significant upregulated in patients compared to HDs (p&lt;.01, |log2FoldChange|&gt;1.2) (Figure 1D). The largest part of the genes involved in inflammation, lipid catabolism, and monocytes activation are less expressed in AOSD patients when compared to COVID19 patients, as reported in Table 1. Table 1. Gene symbol Log2 fold change p Adjusted p Counts COVID19 Counts AOSD Inflammation-related genes ALOX5 0.98 0.024 0.21 16861.61 8562.92 IL13RA1 1.28 0.002 0.053 7154.78 2938.95 RTN3 0.72 0.002 0.0069 9948.37 6045.92 SSH2 1.05 6,78 E-7 0.00016 18343.86 8848.67 Lipid catabolism genes PLBD1 1.68 0.00011 0.0082 28051.88 8671.3 CYP4F3 2.85 0.00034 0.017 1996.63 277.13 STS 1.53 0.010 0.036 1798.5 623.9 HADHA 0.74 0.00014 0.0097 12766.44 7625.38 Monocytes-related genes ALDH2 1.46 2.48E-10 1.85E-07 9186.55 3340.87 CD163 2.37 9,99E-06 0.0014 66499.45 12870.59 MGST1 1.13 0.0026 0.063 1385.54 631.67 RNASE4 2.48 0.0001 0.0092 86.66 15.42 Figure 1. Conclusion The counterbalance by SPMs during inflammation is still a largely unexplored pathway. Our study suggests that an imbalance of SPMs in autoinflammatory diseases as well as COVID-19. The modulation of SPMs as observed in our experiments, might represent a new possible therapeutic strategy during AOSD and COVID-19. References [1]Morita M et al. The lipid mediator protectin D1 inhibits influenza virus replication and improves severe influenza. Cell. 2013;153:112-25. Disclosure of Interests luca navarini Speakers bureau: AbbVie, Pfizer, MSD, UCB, GSK, BMS, Roche, Sanofi Aventis, Novartis, Janssen, Galapagos, Eli Lilly, Paid instructor for: AbbVie, Eli Lilly, Consultant of: Philogen, Grant/research support from: AbbVie, Marta Vomero: None declared, Onorina Berardiucrti: None declared, Damiano Currado: None declared, Annalisa Marino: None declared, Alice Biaggi: None declared, Stefano Di Donato: None declared, Francesco Ursini: None declared, Piero Ruscitti: None declared, Riccardo Meliconi: None declared, Paola Cipriani: None declared, Annamaria Iagnocco Speakers bureau: AbbVie, Pfizer, MSD, UCB, GSK, BMS, Roche, Sanofi Aventis, Novartis, Janssen, Galapagos, Eli Lilly, Antonella Afeltra Speakers bureau: AbbVie, Pfizer, MSD, UCB, GSK, BMS, Roche, Sanofi Aventis, Novartis, Janssen, Galapagos, Eli Lilly, Roberto Giacomelli Speakers bureau: AbbVie, Pfizer, MSD, UCB, GSK, BMS, Roche, Sanofi Aventis, Novartis, Janssen, Galapagos, Eli Lilly, SOBI, Consultant of: Philogen, Grant/research support from: AbbVie, SOBI